Iosimenol, N,N′-bis[3-carbamoyl-5-(2,3-dihydroxypropyl-carbamoyl)-2,4,6-triiodophenyl]-N,N′-bis(2,3-dihydroxypropyl)-malonamide, having the structure showed below, has been proposed as a useful nonionic X-ray contrast agent by Dr. Milos Sovak in 1995 (Patent Literature 1).

In order to make iosimenol fit for commercial use as an X-ray contrast agent, it is necessary to manufacture iosimenol in a high yield and then purify the product effectively. Furthermore, an X-ray contrast agent is generally given to a human body in high dose, thus iosimenol as an X-ray contrast agent is specifically required to be in a high purity. However, it has been difficult to purify such a large amount of iosimenol effectively because iosimenol has chiral centers and pseudoasymmetric carbon atom in the bridge and chiral axes.
Patent Literature 2 discloses some synthetic processes of iosimenol. In Patent Literature 2 (Example 9), iosimenol was prepared by reacting 5,5′-[(1,3-dioxo-1,3-propanediyl)diimino]bis[N-(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide] (hereinafter, referred to as “CVI”) with 3-chloro-1,2-propanediol in water, but the yield was low and the purity of the product was low.
Further, the crude iosimenol was purified through the following steps: deionization, ion-exchange resin adsorption, charcoaling finished by purification using LC reverse phase chromatography (Example 10). The average achieved HPLC purity was around 95% when starting from 85% deionized crude iosimenol.

Patent Literature 1 also discloses a process of preparing iosimenol as shown below. In the process, CVI was protected with isopropylidene beforehand, and then the protected CVI (CVI diacetonide) was reacted with 3-chloro-1,2-propanediol in methanol. The present inventors actually reviewed the process, but both of the yield and the purity were low.

As mentioned above, it is important to manufacture iosimenol in a high purity for a commercial purpose, thus it is necessary to purify a crude product of iosimenol in some way. For manufacturing process, however, there are some real limitations to purify iosimenol using HPLC. It is evident, that the HPLC method represents a powerful and efficient method to reach purity requirements. On the other hand, the HPLC methods have many disadvantages such as low yield, extremely high amount of aqueous waste containing organic solvents (1,000 kg per kg of purified material), and enormously high investment costs. Combination of all these disadvantages constitutes outstandingly high production costs.
Crystallization is one of conventional methods for purification of an active pharmaceutical ingredient (API) of contrast media (CM). Although this method is applied on many ionic CM without difficulties for both monomers and dimers, its application on nonionic CM is not so easy and usually requires very specific conditions. Indeed in Patent Literature 1 and Patent Literature 2, there are no descriptions of any crystals of iosimenol.
It is known that some nonionic CM exist in various isomeric forms and large number of these isomers coexists in obtained solid phase.
Specifically, iosimenol provides three types of stereoisomers:
(A) diastereomers and enantiomers from chiral carbon atoms in the side chains or pseudoasymmetric carbon atom in the bridge and chiral axes;
(B) torsion diastereomers (rotamers) as exo/endo isomerism, cis/trans isomerism, syn/anti isomerism and chiral axes;
(C) conformers.
The present inventors applied crystallization methods described in literature, but this approach always failed, independently on using crude or purified iosimenol. If any solid was obtained, we usually obtained solid of gummy consistency and we never observed any purity increase. Also, iosimenol unlike other contrast agent iodixanol or iohexol is practically insoluble in such solvents as alcohols, ethers and alkoxyalcohols. Usual approach like evaporative crystallization or cooling crystallization failed due to either already-mentioned insolubility of iosimenol in selected solvents or extremely high solubility in aprotic solvents like dimethylformamide.